| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Experimental Therapeutics, Preclinical Pharmacology |
Division of Hematology and Oncology, Department of Medicine and Ireland Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106-4937
Previously we showed that a mismatch repair (MMR)-deficient cell line, HCT116 (hMLH1 mut), unlike a MMR wild-type cell line, SW480, was more resistant to the therapeutic methylating agent, temozolomide (TMZ), because the MMR complex fails to recognize TMZ-induced O6-methylguanine DNA adduct mispairings with thymine that arise after replication. TMZ also produces N7-methylguanine and N3-methyladenine adducts that are processed efficiently by the base excision repair (BER) system. After removal of the methylated base by methylpurine glycosylase, which creates the abasic or apurinic-apyrimidinic (AP) site, the phosphodiester bond is hydrolyzed immediately by AP endonuclease, initiating the repair of the AP site. Methoxyamine (MX) reacts with the abasic site and prevents AP endonuclease cleavage, disrupting DNA repair. MX potentiated the cytotoxic effect of TMZ with a dose modification factor (DMF) of 2.3 ± 0.12 in SW480 and 3.1 ± 0.16 in HCT116. When combined with O6-benzylguanine (BG), MX and TMZ dramatically increased TMZ cytotoxicity (65.8-fold) in SW480, whereas no additive effect was seen in HCT116. This suggests that N7-methylguanine and N3-methyladenine adducts are cytotoxic lesions in MMR-deficient and wild-type cells when BER is interrupted.
Because poly(ADP-ribose) polymerase (PARP) aids in processing of DNA strand breaks induced during MMR and BER, we asked whether PARP inhibitors would also affect BER-mediated cell killing. We found that PARP inhibitors PD128763, 3-aminobenzimide, and 6-aminonicotinamide increased the sensitivity to TMZ in both HCT116 MMR-deficient cells and SW480 MMR wild-type cells. In HCT116 cells, PD128763 remarkably decreased resistance to TMZ, with a DMF of 4.7 ± 0.2. However, the combination of PD128763, BG, and TMZ had no greater effect, indicating that persistent O6-methylguanine had no effect on cytotoxicity. In SW480, the DMF for TMZ cytotoxicity was 3.1 ± 0.12 with addition of PD128763 and 36 with addition of PD128763 and BG. Synergy analysis by median effect plots indicated a high degree of synergy between TMZ and MX or PD128763. In contrast, 1,3-bis(2-chloroethyl)-1-nitrosourea combined with either MX or PD128763 showed little if any potentiation observed in the absence of BG in either cell line, suggesting that BER pathway has little impact on cytotoxic processing of 1,3-bis(2-chloroethyl)-1-nitrosourea-induced adducts. These studies indicate that targeting BER with MX or PARP inhibitors enhances the cytotoxicity of methylating agents, even in MMR-deficient cells.
This article has been cited by other articles:
|
|
 |
|
  M. E. Hegi, L. Liu, J. G. Herman, R. Stupp, W. Wick, M. Weller, M. P. Mehta, and M. R. Gilbert Correlation of O6-Methylguanine Methyltransferase (MGMT) Promoter Methylation With Clinical Outcomes in Glioblastoma and Clinical Strategies to Modulate MGMT Activity J. Clin. Oncol., September 1, 2008; 26(25): 4189 - 4199. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Yamauchi, M. Ogawa, and T. Ueda Carmustine-Resistant Cancer Cells Are Sensitized to Temozolomide As A Result of Enhanced Mismatch Repair during the Development of Carmustine Resistance Mol. Pharmacol., July 1, 2008; 74(1): 82 - 91. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Miknyoczki, H. Chang, J. Grobelny, S. Pritchard, C. Worrell, N. McGann, M. Ator, J. Husten, J. Deibold, R. Hudkins, et al. The selective poly(ADP-ribose) polymerase-1(2) inhibitor, CEP-8983, increases the sensitivity of chemoresistant tumor cells to temozolomide and irinotecan but does not potentiate myelotoxicity Mol. Cancer Ther., August 1, 2007; 6(8): 2290 - 2302. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. P. Cahill, K. K. Levine, R. A. Betensky, P. J. Codd, C. A. Romany, L. B. Reavie, T. T. Batchelor, P. A. Futreal, M. R. Stratton, W. T. Curry, et al. Loss of the Mismatch Repair Protein MSH6 in Human Glioblastomas Is Associated with Tumor Progression during Temozolomide Treatment Clin. Cancer Res., April 1, 2007; 13(7): 2038 - 2045. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Yan, A. Bulgar, Y. Miao, V. Mahajan, J. R. Donze, S. L. Gerson, and L. Liu Combined Treatment with Temozolomide and Methoxyamine: Blocking Apurininc/Pyrimidinic Site Repair Coupled with Targeting Topoisomerase II{alpha} Clin. Cancer Res., March 1, 2007; 13(5): 1532 - 1539. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Fishel, Y. He, M. L. Smith, and M. R. Kelley Manipulation of Base Excision Repair to Sensitize Ovarian Cancer Cells to Alkylating Agent Temozolomide Clin. Cancer Res., January 1, 2007; 13(1): 260 - 267. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ueno, S. H. Ko, E. Grubbs, Y. Yoshimoto, C. Augustine, Z. Abdel-Wahab, T.-Y. Cheng, O. I. Abdel-Wahab, S. K. Pruitt, H. S. Friedman, et al. Modulation of chemotherapy resistance in regional therapy: a novel therapeutic approach to advanced extremity melanoma using intra-arterial temozolomide in combination with systemic O6-benzylguanine. Mol. Cancer Ther., March 1, 2006; 5(3): 732 - 738. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Liu and S. L. Gerson Targeted Modulation of MGMT: Clinical Implications Clin. Cancer Res., January 15, 2006; 12(2): 328 - 331. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. L. Cheng, S. P. Johnson, S. T. Keir, J. A. Quinn, F. Ali-Osman, C. Szabo, H. Li, A. L. Salzman, M. E. Dolan, P. Modrich, et al. Poly(ADP-ribose) polymerase-1 inhibition reverses temozolomide resistance in a DNA mismatch repair-deficient malignant glioma xenograft Mol. Cancer Ther., September 1, 2005; 4(9): 1364 - 1368. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Liu, Y. Guo, Y. Li, Y. Jiang, S. Chubb, A. Azuma, P. Huang, A. Matsuda, W. Hittelman, and W. Plunkett Molecular Basis for G2 Arrest Induced by 2'-C-Cyano-2'-Deoxy-1-{beta}-D-Arabino-Pentofuranosylcytosine and Consequences of Checkpoint Abrogation Cancer Res., August 1, 2005; 65(15): 6874 - 6881. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. K. Horton, D. F. Stefanick, J. M. Naron, P. S. Kedar, and S. H. Wilson Poly(ADP-ribose) Polymerase Activity Prevents Signaling Pathways for Cell Cycle Arrest after DNA Methylating Agent Exposure J. Biol. Chem., April 22, 2005; 280(16): 15773 - 15785. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Rinne, D. Caldwell, and M. R. Kelley Transient adenoviral N-methylpurine DNA glycosylase overexpression imparts chemotherapeutic sensitivity to human breast cancer cells Mol. Cancer Ther., August 1, 2004; 3(8): 955 - 967. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. J. Curtin, L.-Z. Wang, A. Yiakouvaki, S. Kyle, C. A. Arris, S. Canan-Koch, S. E. Webber, B. W. Durkacz, H. A. Calvert, Z. Hostomsky, et al. Novel Poly(ADP-ribose) Polymerase-1 Inhibitor, AG14361, Restores Sensitivity to Temozolomide in Mismatch Repair-Deficient Cells Clin. Cancer Res., February 1, 2004; 10(3): 881 - 889. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Vera, L. Djafari, S. Faivre, J.-S. Guillamo, K. Djazouli, M. Osorio, F. Parker, C. Cioloca, B. Abdulkarim, J.-P. Armand, et al. Dose-dense regimen of temozolomide given every other week in patients with primary central nervous system tumors Ann. Onc., January 1, 2004; 15(1): 161 - 171. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Hirose, M. Katayama, D. Stokoe, D. A. Haas-Kogan, M. S. Berger, and R. O. Pieper The p38 Mitogen-Activated Protein Kinase Pathway Links the DNA Mismatch Repair System to the G2 Checkpoint and to Resistance to Chemotherapeutic DNA-Methylating Agents Mol. Cell. Biol., November 15, 2003; 23(22): 8306 - 8315. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Tentori, C. Leonetti, M. Scarsella, G. d'Amati, M. Vergati, I. Portarena, W. Xu, V. Kalish, G. Zupi, J. Zhang, et al. Systemic Administration of GPI 15427, a Novel Poly(ADP-Ribose) Polymerase-1 Inhibitor, Increases the Antitumor Activity of Temozolomide against Intracranial Melanoma, Glioma, Lymphoma Clin. Cancer Res., November 1, 2003; 9(14): 5370 - 5379. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Liu, L. Yan, J. R. Donze, and S. L. Gerson Blockage of abasic site repair enhances antitumor efficacy of 1,3-bis-(2-chloroethyl)-1-nitrosourea in colon tumor xenografts Mol. Cancer Ther., October 1, 2003; 2(10): 1061 - 1066. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Miknyoczki, S. Jones-Bolin, S. Pritchard, K. Hunter, H. Zhao, W. Wan, M. Ator, R. Bihovsky, R. Hudkins, S. Chatterjee, et al. Chemopotentiation of Temozolomide, Irinotecan, and Cisplatin Activity by CEP-6800, a Poly(ADP-Ribose) Polymerase Inhibitor Mol. Cancer Ther., April 1, 2003; 2(4): 371 - 382. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Taverna, H.-s. Hwang, J. E. Schupp, T. Radivoyevitch, N. N. Session, G. Reddy, D. A. Zarling, and T. J. Kinsella Inhibition of Base Excision Repair Potentiates Iododeoxyuridine-induced Cytotoxicity and Radiosensitization Cancer Res., February 15, 2003; 63(4): 838 - 846. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Tentori, I. Portarena, M. Barbarino, A. Balduzzi, L. Levati, M. Vergati, A. Biroccio, B. Gold, M. L. Lombardi, and G. Graziani Inhibition of Telomerase Increases Resistance of Melanoma Cells to Temozolomide, but Not to Temozolomide Combined with Poly (ADP-Ribose) Polymerase Inhibitor Mol. Pharmacol., January 1, 2003; 63(1): 192 - 202. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Liu, Y. Nakatsuru, and S. L. Gerson Base Excision Repair as a Therapeutic Target in Colon Cancer Clin. Cancer Res., September 1, 2002; 8(9): 2985 - 2991. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. L. Gerson Clinical Relevance of MGMT in the Treatment of Cancer J. Clin. Oncol., May 1, 2002; 20(9): 2388 - 2399. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Tentori, C. Leonetti, M. Scarsella, G. d'Amati, I. Portarena, G. Zupi, E. Bonmassar, and G. Graziani Combined treatment with temozolomide and poly(ADP-ribose) polymerase inhibitor enhances survival of mice bearing hematologic malignancy at the central nervous system site Blood, March 15, 2002; 99(6): 2241 - 2244. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. S. Friedman, T. Kerby, and H. Calvert Temozolomide and Treatment of Malignant Glioma Clin. Cancer Res., July 1, 2000; 6(7): 2585 - 2597. [Abstract] [Full Text]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
